The immune response to polysaccharide (PS) antigens is highly regulated and has several distinguishing features including restricted subclass, variable region gene usage, fine specificity, and avidity. Simple PS not conjugated to protein (such as bacterial levan (BL) or Neisseria meningitidis group C (MCPS)) elicit a thymus-independent (TI) response. Our earlier studies of the TI-response to BL in two strains of mice showed strain-specific differences in monoclonal antibody (mAb) V gene family usage, fine specificity, and immunization protocol. BALB/c mAb were primarily VHJ606/VK11 and cross-reacted with inulin (In). CBA/Ca mAb used VHJ606 and VK11 genes separately, and could cross-react with In, but primarily did not. DNA sequence and avidity studies indicated that primary BALB/c mAb in general were germline (V14A gene), used identical DH and JH, and were low avidity. BALB/c mAb to two injections of BL were somatically mutated and higher avidity. Oligomer hybridization to genomic DNA indicated that CBA/Ca do not possess the V14A germline gene used by BALB/c mAb. CBA/Ca mAb used a variety of DH and JH gene segments and were somatically mutated. Ongoing studies include site directed mutagenesis, chain recombination, and germinal center analysis in both strains. PS conjugated to proteins (such as MCPS coupled to tetanus toxoid (MCPS-TT)), on the other hand, elicit a different type of response termed thymus-dependent (TD). Recent studies have shown that monoclonal antibodies derived from mice immunized twice with a thymus-independent polysaccharide antigen can exhibit somatic mutations and affinity maturation, features previously thought to be associated only with antibody responses to thymus-dependent protein antigens. This finding could lead to better immunization strategies of polysaccharide or polysaccharide-protein conjugate vaccines.